Oligopeptides, the preparation and use thereof

ABSTRACT

Novel peptides of the formula 
     
         A--B--D--E--F--L, 
    
     wherein A, B, D, E, F, and L have the meanings stated in the specification, and their preparation are disclosed. The novel compounds are suitable for controlling diseases.

It is known that peptides isolated from marine origin like Dolastatin-10 (U.S. Pat. No. 4,816,444) and Dolastatin-15 (EP-A-398558) show potent cell growth inhibitory activity cf.: Biochem. Pharmacology 40, 1859-64 (1990); J. Natl. Cancer Inst. 85, 483-88 (1993) and references cited therein!. Based upon interesting results in experimental tumor systems in vivo further preclinical evaluation of these natural products is currently under way to initiate clinical studies in cancer patients. Due to laborious purification processes from scarce natural sources alternative access to these peptides has been investigated by synthetic routes cf.: Tetrahedron 50, 5345-60 (1994) Tetrahedron 49, 1913-24 (1993); Tetrahedron 48, 4115-22 (1992) and references cited therein!.

Since the natural products show disadvantages as poor solubility in aqueous solvents and costly building blocks, structural modifications have been investigated cf.: Bioorganic & Med. Chem. Lett. 4, 1947-50 (1994); WO 93 03054; JP-A-06234790, EP (O.Z. 43202)!.

The invention described herein provides novel oligopeptides and derivatives thereof which offer a surprisingly improved therapeutic potential for the treatment of neoplastic diseases as compared to Dolastatin-10 and -15 with activity even in MDR resistant tumor systems and with an unpredicted high solubility in aqueous solvents. Furthermore, the compounds of the present invention may be conveniently synthesized as described below in detail.

Compounds of the present invention include peptides of the formula I

    A--B--D--E--F--L                                           (I)

and the salts thereof with physiologically tolerated acids, wherein A, B, D, E, F and L have the following meanings: ##STR1## where R_(A) is hydrogen, C₁₋₃ -alkyl which can be substituted by 1 to 3 fluorine atoms or cyclopropyl which can be substituted by 1 to 3 fluorine atoms,

R¹ _(A) is C₁₋₃ -alkyl which can be substituted by 1 to 3 fluorine atoms or cyclopropyl which can be substituted by 1 to 3 fluorine atoms,

R² _(A) is C₁₋₅ -alkyl which can be substituted by 1 to 3 fluorine atoms, or C₃₋₅ -cycloalkyl which can be substituted by 1 to 3 fluorine atoms, or ##STR2## where either T is an NH group,

R¹ _(B) is hydrogen,

R² _(B) is C₁₋₆ -alkyl, C₃₋₆ -cycloalkyl, methoxymethyl, 1-methoxyethyl or 1-methylvinyl, or

R¹ _(B) and R² _(B) together are an isopropylidene group, or

T is an oxygen atom,

R¹ _(B) is hydrogen and

R² _(B) is C₁₋₆ -alkyl; ##STR3## where R_(D) is hydrogen, C₁₋₃ -alkyl which can be substituted by 1 to 3 fluorine atoms or cyclopropyl which can be substituted by 1 to 3 fluorine atoms,

R¹ _(D) is hydrogen and

R² _(D) is C₁₋₅ -alkyl, cyclo-propyl, methoxymethyl, 1-methoxyethyl or 1-methyl-vinyl, or ##STR4## where n_(E) is 0, 1 or 2,

R¹ _(E) is hydrogen or C₁₋₃ -alkyl which can be substituted by 1 to 3 fluorine atoms or cyclopropyl which can be substituted by 1 to 3 fluorine atoms,

R² _(E) and R³ _(E) are, independently of one another, hydrogen or a methyl group,

R⁴ _(E) is hydrogen, a hydroxy, methoxy or ethoxy group or a fluorine atom, and

R⁵ _(E) is hydrogen or a fluorine atom or, if n_(E) is 1,

R³ _(E) and R⁴ _(E) together are a bond, or

R⁴ _(E) and R⁵ _(E) are a doubly bonded oxygen radical, or, if n_(E) is 2,

R¹ _(E) and R² _(E) together are a bond; ##STR5## where R_(E) is hydrogen or a methyl or ethyl group, and

R¹ _(E) is hydrogen, C₁₋₃ -alkyl which can be substituted by 1 to 3 fluorine atoms or cyclopropyl which can be substituted by 1 to 3 fluorine atoms, or E a residue of the formula ##STR6## wherein X_(E) is an oxygen or a sulfur atom ##STR7## where n_(F) is 0, 1 or 2,

R¹ _(F) is hydrogen or C₁₋₃ -alkyl which can be substituted by 1 to 3 fluorine atoms or cyclopropyl which can be substituted by 1 to 3 fluorine atoms,

R² _(F) and R³ _(F) are, independently of one another, hydrogen or a methyl group,

R⁴ _(F) is hydrogen, a hydroxy, methoxy or ethoxy group or a fluorine atom, and

R⁵ _(F) is hydrogen or a fluorine atom or, if n_(F) is 1,

R³ _(F) and R⁴ _(F) together are a bond, or ##STR8## where R_(f) is hydrogen or a methyl or ethyl group, and

R¹ _(F) is C₁₋₃ -alkyl which can be substituted by 1 to 3 fluorine atoms or cyclopropyl which can be substituted by 1 to 3 fluorine atoms, or ##STR9## wherein X_(F) is oxygen or sulfur F: an N-methylglycyl, N-ethylglycyl or -alanyl radical,

L: a substituted or unsubstituted, hydroxylamino, or oxime residue.

In one embodiment, L is a radical of the formula I_(L)

    --OR.sub.L (I.sub.L)

wherein R_(L) is a C₃₋₁₀ -cycloalkyl, C₂₋₁₈ -methylalkenyl, C₅₋₁₆ -alkyl or C₁₋₁₅ -alkylcarboxy-C₁₋₁₀ -alkyl group, which can, optionally, be substituted by from 1 to 5 halogen atoms. R_(L) can also be the radical --(CH₂)_(aL) --R¹ _(L) where a_(L) is 1, 2 or 3. R¹ _(L) is a saturated or partially unsaturated C₃₋₁₀ -carbocycle or a saturated or partially unsaturated C₃₋₁₀ cyclic radical which, in addition to carbon atoms, includes one or more heteroatoms selected from among oxygen, nitrogen and sulfur as ring members. In saturated systems which Include a nitrogen atom, the nitrogen atom can be bonded to a C₁₋₄ -alkyl, C₁₋₄ -acyl, C₁₋₄ -alkoxyacyl, benzyl or benzoyl group.

R_(L) can also be the radical -- CH₂ --CH═C(CH₃)--CH₂ !_(bL) --H where b_(L) is 1-4. R_(L) can also be the radical --(CH₂ --CH₂ --O)_(dL) --CH₃, wherein d_(L) is 1-5.

If R_(L) is --(CH₂)_(eL) -aryl, eL is 0, 1, 2 or 3 and then aryl is preferably phenyl or naphthyl, and suitable substituents are: halogen atoms, preferably fluorine, bromine or chlorine, C₁ -C₄ -alkyl groups, trifluoromethyl, C₁ -C₄ -alkoxy groups, trifluoromethoxy, dioxymethylene or -ethylene, a nitro or cyano group, C₁ -C₄ -alkoxycarbonyl, a C₁ -C₇ -alkylsulfonyl group, an amino or C₁ -C₇ -dialkylamino group in which the alkyl radicals can also together form a heterocycle. Hetaryl is preferably a 5- to 6-membered ring system which preferably contains nitrogen, oxygen and/or sulfur atoms and may be fused to a benzene ring, such as the imidazole, pyrrole, thiophene, furan, thiazole, oxazole, pyrazole, 1,2,4- or 1,2,3-triazole, oxadiazole, thiadiazole, isoxazole, isothiazole, pyrazine, pyridazine, pyrimidine, pyridine, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzopyran, indole, isoindole, indazole or quinoline residue, the preferred substituents being C₁ -C₄ -alkyl groups, or the hydroxyl or phenyl radical.

If R_(L) ² is substituted aryl or methylaryl, the substituents preferably have the following meanings:

halogen atoms, C₁ -C₄ -alkyl, trifluoromethyl, C₁ -C₄ -alkoxy groups, trifluoromethoxy, dioxymethylene or -ethylene, a nitro or cyano group, C₁ -C₄ -alkoxycarbonyl, a C₁ -C₇ -alkylsulfonyl group, an amino or C₁ -C₇ -dialkylamino group, in which the alkyl radicals can also together form a heterocycle.

If R_(L) ³ is substituted aryl or methylaryl, the substituents preferably have the following meanings:

halogen atoms, C₁ -C₄ -alkyl, trifluoromethyl, C₁ -C₄ -alkoxy groups, trifluoromethoxy, dioxymethylene or -ethylene, a nitro or cyano group, C₁ -C₄ -alkoxycarbonyl, a C₁ -C₇ -alkylsulfonyl group, an amino or C₁ -C₇ -dialkylamino group, in which the alkyl radicals can also together form a heterocycle.

Another group of compounds according to the invention includes peptide derivatives of the formula I where

L is a hydroxylamine residue of the formula ##STR10## where R_(L) ⁵ is hydrogen, straight-chain or branched C₁ -C₈ -alkyl which can be substituted by up to 6 halogen atoms, preferably fluorine, or C₃₋₁₀ -cycloalkyl or C₁₋₄ -alkyl-C₃₋₁₀ -cycloalkyl, substituted or unsubstituted aryl or hetaryl or substituted or unsubstituted C₁₋₄ -alkylaryl with the substituents having the meanings stated for R_(L), and

R_(L) ⁶ has one of the meanings stated for R_(L) ⁵, where R_(L) ⁵ and R_(L) ⁶ are not both hydrogen, or

R_(L) ⁵ and R_(L) ⁶ together with the N atom form a 5-, 6- or 7-membered heterocycle, and the salts thereof with physiologically tolerated acids.

Another group of compounds according to the invention includes peptide derivatives of the formula I as claimed in claim 1, where

L is an oxime residue of the formula VI_(L) ##STR11## where R_(L) ⁵ and R_(L) ⁶ have the abovementioned meanings, or ##STR12## R_(L) ⁵ and R_(L) ⁶ together with the C atom form a 3- to 7-membered cyclic system which may be aromatic-fused, and the salts thereof with physiologically tolerated acids.

Preferred cyclic systems are: ##STR13##

These examples illustrate but do not limit the scope of the present invention.

The peptides of the formula I are composed of L-amino acids but they may contain one or more D-amino acids.

The new compounds may be present as salts with physiologically tolerated acids such as: hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine.

Particularly preferred compounds are those where the radicals have the following meanings:

R_(A) : hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, 2,2,2-trifluoroethyl, 2-fluoroethyl;

R¹ _(A) : hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, 2,2,2-trifluoroethyl, 2-fluoroethyl;

R² _(A) : hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, cyclopropyl, cyclobutyl, 2,2,2-trifluoroethyl, 2-fluoroethyl;

T an NH group and

R¹ _(B) hydrogen,

R² _(B) cyclopropyl, ethyl, isopropyl, butyl, tert-butyl, sec.-butyl, methoxymethyl, 1-methoxyethyl, 1-methylvinyl;

or R¹ _(B) and R² _(B) together an isopropylidene group, or

T an oxygen atom and

R¹ _(B) hydrogen;

R² _(B) methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl;

R_(D) : hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, 2,2,2-trifluoroethyl, 2-fluoroethyl;

R¹ _(D) hydrogen;

R² _(D) methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, 3-methylbutyl, 2,3-dimethylpropyl, cyclopropyl, cyclobutyl, methoxymethyl, 1-methoxyethyl, 1-methylvinyl, or

E is a substituted azetidinyl, pyrrolidinyl or piperidinyl radical of the following formula: ##STR14## where R¹ _(E) is hydrogen, C₁₋₃ -alkyl which can be substituted by 1 to 3 fluorine atoms or cyclopropyl which can be substituted by 1 to 3 fluorine atoms,

R² _(E) and R³ _(E) are, independently of one another, a hydrogen atom or a methyl group;

R⁴ _(E) is hydrogen, a hydroxyl group, a methoxy or ethoxy radical or a fluorine atom;

R⁵ _(E) is hydrogen or fluorine or

E is a substituted aminocyclopentylcarbonyl radical of the following formula: ##STR15## where R^(E) is hydrogen methyl or ethyl, and

R¹ _(E) is C₁₋₃ -alkyl which can be atoms or cyclopropyl which can be substituted by 1 to 3 fluorine atoms,

F has the meanings stated for E or is a radical of the formula ##STR16##

Very particularly preferred peptides of the formula

    A--B--D--E--F--L                                           (I),

are those where the radicals have the following meanings: ##STR17## where R_(A) and R¹ _(A) have the abovementioned meanings; ##STR18## where R_(D) has the abovementioned meanings, ##STR19## T¹⁰ is hydrogen, C₁₋₃ -alkyl which can be substituted by 1 to 3 fluorine atoms or cyclopropyl which can be substituted by 1 to 3 fluorine atoms.

F has the meanings stated for E.

The radical L is preferably a radical of the formula --O--R_(L) where the radical R_(L) is preferably C₃ -C₁₆ -alkyl such as

pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, 1-methylethyl, 2-methylbutyl, 3-methylbutyl, 2-methylpropyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 4-methylpentyl, 4,4-dimethylpentyl, 3-pentyl, 4-heptyl, 2,2,2-trifluoroethyl, 1-fluoroethyl, 2,2-difluoroethyl, 1,3-difluoro-2-propyl

C₃ -C₁₀ -cycloalkyl, such as

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl.

Methyl-, ethyl- or propyl-(C₃ -C₁₀)-cycloalkyl; methyladamantyl; C₂ -C₁₆ -alkenyl, such as

2-propenyl, 3-butenyl, 2-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-methyl-2-propenyl, 3-pentenyl, 4-pentenyl, 2-methyl-2-butenyl, 3,7-dimethyl-2,6-octadienyl, 3,7,11-trimethyldodeca-2,6,10-trienyl, 3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl;

a saturated heterocycle such as ##STR20## 2-methoxyethyl, 2-(2-methoxy-ethoxy)ethyl, 2- 2-(2-methoxy-ethoxy)ethoxy!ethyl, 2-{2- 2-(2-methoxy-ethoxy)ethoxy!ethoxy}ethyl;

R_(L) is also preferably radicals such as aryl, methylaryl, ethylaryl, propylaryl, where aryl can be substituted or unsubstituted.

Aryl is preferably a phenyl or naphthyl radical of the formula ##STR21## where suitable substituents T_(L) ¹ and T_(L) ² are independently of one another, the following radicals (with the proviso that R_(L) is not phenyl):

H, Cl, F, Br, C₁₋₄ -alkyl, C₁₋₄ -alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, dioxymethylene or -ethylene, C₁₋₇ -alkoxycarbonyl, C₁₋₇ -alkylsulfonyl, amino or C₁₋₇ -dialkylamino, in which the alkyl groups can together form a heterocycle; or methylhetaryl, ethylhetaryl, propylhetaryl, where hetaryl can be substituted or unsubstituted.

Hetaryl is preferably: ##STR22## with T_(L) ³ =H, OH, C₁₋₄ -alkyl, phenyl, a straight-chain or branched C₁₋₅ -alkylcarbonyl-, C₁₋₁₀ -alkoxy group such as: ##STR23## with T_(L) ⁴ =C₁₋₄ -alkyl; a radical of the formula ##STR24## with T_(L) ⁵ =H, C₁₋₄ -alkyl, C₁₋₆ -cycloalkyl, ##STR25## with T_(L) ⁶ having the meanings stated for T_(L) ⁵ and additionally being C₁₋₄ -acyl, benzoyl, tert-butyloxycarbonyl, benzyloxycarbonyl, ##STR26## with T_(L) ⁷ =CHO, NHCHO, NHNHCHO, or a radical of the formula ##STR27## with T_(L) ⁸, T_(L) ⁹ =OCH₃, OC₂ H₅, SCH₃, SC₂ H₅, or T_(L) ⁸ and T_(L) ⁹ together with the C atom they are connected to form a cyclic system of the formula ##STR28## with R_(L) ⁴ being a polyethylene glycol ester of the formula --O--(CH₂ CH₂ O)_(hL) --CH₃ with hL being a number from 40 to 90.

Another group includes substances where L is a hydroxylamine residue of the formula ##STR29## where R_(L) ⁵ is preferably hydrogen, methyl, ethyl, propyl, butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, 2-methylbutyl, 3-methylbutyl, 2-methylethyl, 2-methylpropyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 4-methylpentyl, 4,4-dimethylpentyl, 2,2,2-trifluoroethyl, 1-fluoroethyl, 2,2-difluoroethyl, C₃₋₈ -cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl; methyl-, ethyl-, propyl-, butyl-C₃₋₁₀ -cycloalkyl,

a substituted or unsubstituted aryl or hetaryl radical or an C₁₋₄ -alkyl-aryl- or -hetaryl with the meanings stated for R_(L) ; and

R_(L) ⁶ is Z methyl, ethyl, propyl, butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, 2-methylbutyl, 3-methylbutyl, 2-methylethyl, 2-methylpropyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 4-methylpentyl, 4,4-dimethylpentyl, 2,2,2-trifluoroethyl, 1-fluoroethyl, 2,2-difluoroethyl, C₃₋₈ -cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl; methyl-, ethyl-, propyl-, butyl-C₃₋₁₀ -cycloalkyl, or R_(L) ⁵ --N--R_(L) ⁶ form a cyclic system with the following formula: ##STR30##

Another group of preferred compounds includes oxime esters of the formula ##STR31## where R_(L) ⁵ and R_(L) ⁶ have the abovementioned meanings, or ##STR32## form a cyclic system of the following formula: ##STR33##

In general,

C₁₋₄ -alkyl is methyl, ethyl, propyl, 2-methylethyl, butyl, tertbutyl, 3-methylpropyl;

C₁₋₄ -alkoxy is methoxy, ethoxy, propoxy, butoxy, tert-butoxy, 2-methylethoxy, 3-methylpropoxy;

C₁₋₄ -alkylsulfonyl is --SO₂ CH₃, --SO₂ C₂ H₅, --SO₂ C₃ H₇, --SO₂ C₄ H₉, --SO₂ C₅ H₁₁, --SO₂ C₆ H₁₃, --SO₂ C₇ H₁₅ ;

a C₁₋₇ -dialkylamino group, where the alkyl radicals can form a common heterocycle is ##STR34## C₃₋₈ -cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

The novel compounds can be prepared by known methods of peptide chemistry. Thus, the peptides can be assembled sequentially from amino acids or by linking suitable small peptide fragments. In the sequential assemblage, starting at the C terminus the peptide chain is extended stepwise by one amino acid each time. In fragment coupling it is possible to link together fragments of different lengths, and the fragments in turn can be obtained by sequential assemblage from amino acids or themselves by fragment coupling.

Both in the sequential assemblage and in the fragment coupling it is necessary to link the units by forming an amide, ester or hydroxylamine linkage. Enzymatic and chemical methods are suitable for this.

Chemical methods for forming the amide linkage are described in detail by Muller, Methoden der organischen Chemie Vol. XV/2, pp 1 to 364, Thieme Verlag, Stuttgart, 1974; Stewart, Young, Solid Phase Peptide Synthesis, pp 31 to 34, 71 to 82, Pierce Chemical Company, Rockford, 1984; Bodanszky, Klausner, Ondetti, Peptide Synthesis, pp 85 to 128, John Wiley & Sons, New York, 1976 and other standard works on peptide chemistry. Particular preference is given to the azide method, the symmetric and mixed anhydride method, in situ generated or preformed active esters, the use of urethane protected N-carboxy anhydrides of amino acids and the formation of the amide linkage using coupling reagents (activators, especially dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), n-propanephosphonic anhydride (PPA), N,N-bis(2-oxo-3-oxazolidinyl)-midophosphoryl chloride (BOP-Cl), bromo-tris-pyrrolidinophosphonium hexa-fluorophosphate (PyBrop), diphenylphosphoryl azide (DPPA), Castro's reagent (BOP, PyBop), O-benzotriazolyl-N,N,N',N'-tetramethyluronium salts (HBTU), diethylphosphoryl cyanide (DEPCN), 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene dioxide (Steglich's reagent; HOTDO) and 1,1'-carbonyldiimidazole (CDI) 7-azabenzotriazolyl-N,N,N',N'-tetramethyluronium salts (HATU: described in THL Vol. 35, No. 33, 5981-5984). The coupling reagents can be employed alone or in combination with additives such as N,N-dimethyl-4-aminopyridine (DMAP), N-hydroxy-benzotriazole (HOBt), 1-hydroxy-7-azabenzotriazol (HOAt), N-hydroxybenzotriazine (HOOBt), N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine.

Formation of the ester or hydroxylamine linkage can be achieved by coupling a suitable amino acid or peptide derivative with a hydroxy- or hydroxylamino compound in the presence of coupling reagent and a base. Particular preference is given to the methods and coupling reagents already described for the formation of the amide linkage. Suitable bases are organic amines, such as N,N-dimethylaminopyridine (DMAP), pyridine, N-methylmorpholine, triethylamine.

Whereas it is normally possible to dispense with protective groups in enzymatic peptide synthesis, reversible protection of reactive groups not involved in formation of the amide linkage is necessary for both reactants in chemical synthesis. Three conventional protective group techniques are preferred for the chemical peptide synthesis: the benzyloxycarbonyl (Z), the t-butoxycarbonyl (Boc) and the 9-fluorenylmethoxycarbonyl (Fmoc) techniques. Identified in each case is the protective group on the α-amino group of the chain-extending unit. A detailed review of amino-acid protective groups is given by Muller, Methoden der organischen Chemie Vol. XV/1, pp 20 to 906, Thieme Verlag, Stuttgart, 1974. The units employed for assembling the peptide chain can be reacted in solution, in suspension or by a method similar to that described by Merrifield in J. Amer. Chem. Soc. 85 (1963) 2149. Particularly preferred methods are those in which peptides are assembled sequentially or by fragment coupling using the Z, Boc or Fmoc protective group technique, with one of the reactants in the said Merrifield technique being bonded to an insoluble polymeric support (also called resin hereinafter). This typically entails the peptide being assembled sequentially on the polymeric support using the Boc or Fmoc protective group technique, the growing peptide chain being covalently bonded at the C terminus to the insoluble resin particles (cf. FIGS. 1 and 2). This procedure makes it possible to remove reagents and byproducts by filtration, and thus recrystallization of intermediates is unnecessary.

The protected amino acids can be linked to any suitable polymers, which merely have to be insoluble in the solvents used and to have a stable physical form which makes filtration easy. The polymer must contain a functional group to which the first protected amino acid can be firmly attached by a covalent bond. Suitable for this purpose are a wide variety of polymers, eg. cellulose, polyvinyl alcohol, polymethacrylate, sulfonated polystyrene, chloromethylated styrene/divinylbenzene copolymer (Merrifield resin), 4-methylbenzhydrylamine resin (MBHA-resin), phenylacetamidomethyl-resin (Pam-resin), p-benzyloxy-benzyl-alcohol-resin, benzhydryl-amine-resin (BHA-resin), 4-(hydroxymethyl)benzoyloxy-methyl-resin, the resin of Breipohl et al. (Tetrahedron Letters 28 (1987) 565; supplied by BACHEM), 4-(2,4-dimethoxyphenylaminomethyl)phenoxy-resin (supplied by Novabiochem) or o-chlorotrityl-resin (supplied by Biohellas).

Suitable for peptide synthesis in solution are all solvents which are inert under the reaction conditions, especially water, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane (DCM), 1,4-dioxane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP) and mixtures of the said solvents. Peptide synthesis on the polymeric support can be carried out in all inert organic solvents in which the amino-acid derivatives used are soluble; however, preferred solvents additionally have resin-swelling properties, such as DMF, DCM, NMP, acetonitrile and DMSO, and mixtures of these solvents. After synthesis is complete, the peptide is cleaved off the polymeric support. The conditions under which cleavage off the various resin types is possible are disclosed in the literature. The cleavage reactions most commonly used are acid- and palladium-catalyzed, especially cleavage in liquid anhydrous hydrogen fluoride, in anhydrous trifluoromethanesulfonic acid, in dilute or concentrated trifluoroacetic acid, palladium-catalyzed cleavage in THF or THF-DCM mixtures in the presence of a weak base such as morpholine or cleavage in acetic acid/dichloromethane/trifluoroethanol mixtures. Depending on the chosen protective groups, these may be retained or likewise cleaved off under the cleavage conditions. Partial deprotection of the peptide may also be worthwhile when certain derivatization reactions are to be carried out. Peptides dialkylated at the N-terminus can be prepared either by coupling of the appropriate N,N-di-alkylamino acids in solution or on the polymeric support or by reductive alkylation of the resin-bound peptide in DMF/1% acetic acid with NaCNBH₃ and the appropriate aldehydes.

The compounds of this invention may be used to inhibit or otherwise treat solid tumors (e.g. tumors of the lung, breast, colon, prostate, bladder, rectum, or endometrial tumors) or hematological malignancies (e.g. leucemias, lymphomas) by administration of the compound to the mammal. Administration may be by any of the means which are conventional for pharmaceutical, preferably oncological, agents, including oral and parenteral means such as subcutaneously, intravenously, intramuscularly and intraperitoneally. The compounds may be administered alone or in the form of pharmaceutical compositions containing a compound of formula I together with a pharmaceutically accepted carrier appropriate for the desired route of administration. Such pharmaceutical compositions may be combination products, i.e., may also contain other therapeutically active ingredients.

The dosage to be administered to the mammal will contain an effective tumor-inhibiting amount of active ingredient which will depend upon conventional factors including the biological activity of the particular compound employed; the means of administration; the age, health and body weight of the recipient; the nature and extent of the symptoms; the frequency of treatment; the administration of other therapies; and the effect desired. A typical daily dose will be about 0.05 to 250 milligrams per kilogram of body weight on oral administration and about 0.05 to 100 milligrams per kilogram of body weight on parenteral administration.

The novel compounds can be administered in conventional solid or liquid pharmaceutical administration forms, eg. uncoated or (film-)coated tablets, capsules, powders, granules, suppositories or solutions. These are produced in a conventional manner. The active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, sustained release compositions, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain 1-90% by weight of the active substance.

The following examples are intended to illustrate the invention. The proteinogenous amino acids are abbreviated in the examples using the known three-letter code. Other meanings are: TFA=trifluoroacetic acid, Ac=acetic acid, Bu=butyl, Et=ethyl, Me=methyl, Bzl=benzyl.

A. General Procedures

I. The peptides claimed in claim 1 are either synthesized by classical solution synthesis using standard Z- and Boc-methodology as described above or by standard methods of solid-phase synthesis on a completely automatic model 431A synthesizer supplied by APPLIED BIOSYSTEMS. The apparatus uses different synthetic cycles for the Boc and Fmoc protective group techniques.

a) Synthetic cycle for the Boc protective group technique

1. 30% trifluoroacetic acid in DCM 1×3 min

2. 50% trifluoroacetic acid in DCM 1×1 min

3. DCM washing 5×1 min

4. 5% diisopropylethylamine in DCM 1×1 min

5. 5% diisopropylethylamine in NMP 1×1 min

6. NMP washing 5×1 min

7. Addition of preactivated protected amino acid (activation with 1 equivalent of DCC and 1 equivalent of HOBt in NMP/DCM); Peptide coupling (1st part) 1×30 min

8. Addition of DMSO to the reaction mixture until it contains 20% DMSO by volume

9. Peptide coupling (2nd part) 1×16 min

10. Addition of 3.8 equivalents of diisopropylethylamine to the reaction mixture

11. Peptide coupling (3rd part) 1×7 min

12. DCM washing 3×1 min

13. if conversion is incomplete, repetition of coupling (back to 5.)

14. 10% acetic anhydride, 5% diisopropylethylamine in DCM 1×2 min

15. 10% acetic anhydride in DCM 1×4 min

16. DCM washing 4×1 min

17. back to 1.

BOP-Cl and PyBrop were used as reagents for coupling of the amino acid following N-methylamino acids. The reaction times were correspondingly increased. In solution synthesis, the use of either Boc-protected amino acid NCAs (N-tert.-butyloxycarbonyl-amino acid-N-carboxy-anhydrides) or Z-protected amino acid NCAs (N-benzyloxycarbonyl-amino acid-N-carboxy-anhydrides) respectively is most advantageous for this type of coupling.

b) Synthetic cycle for the Fmoc protective group technique

1. DMF washing 1×1 min

2. 20% piperidine in DMF 1×4 min

3. 20% piperidine in DMF 1×16 min

4. DMF washing 5×1 min

5. Addition of the preactivated protected amino acid (activation by 1 equivalent of TBTU and 1.5 equivalent of DIPEA in DMF); Peptide coupling 1×61 min

6. DMF washing 3×1 min

7. if conversion is incomplete, repetition of coupling (back to 5.)

8. 10% acetic anhydride in DMF 1×8 min

9. DMF washing 3×1 min

10. back to 2.

BOP-Cl and PyBrop were used as reagents for coupling on the amino acid following the N-methylamino acids. The reaction times were correspondingly increased.

II. Reductive alkylation of the N terminus

The peptide-resin prepared as in AIa or AIb was deprotected at the N terminus (steps 2-4 in AIb or 1-6 in AIa) and then reacted with a 3-fold molar excess of aldehyde or ketone in DMF/1% acetic acid with addition of 3 equivalents of NaCNBH₃. After reaction was complete (negative Kaiser test) the resin was washed several times with water, isopropanol, DMF and dichloromethane.

III. Workup of the peptide-resins obtained as in Ia and II

The peptide-resin was dried under reduced pressure and transferred into a reaction vessel of a TEFLON HF apparatus (supplied by PENINSULA). Addition of a scavenger, preferably anisole (1 ml/g of resin), and in the case of tryptophan-containing peptides of a thiol to remove the indolic formyl group, preferably ethane-dithiol (0.5 ml/g of resin), was followed by condensing in hydrogen fluoride (10 ml/g of resin) while cooling with liquid N₂. The mixture was left to warm to 0° C. and stirred at this temperature for 45 min. The hydrogen fluoride was then stripped off under reduced pressure, and the residue was washed with ethyl acetate in order to remove remaining scavenger. The peptide was extracted with 30% strength acetic acid and filtered, and the filtrate was lyophilized.

IV. Work-up of the peptide-resins obtained as in Ib and II

The peptide-resin was dried under reduced pressure and then subjected to one of the following cleavage procedures, depending on the amino-acid composition (Wade, Tregear, Howard Florey Fmoc Workshop Manual, Melbourne 1985).

    ______________________________________                                         Cleavage conditions                                                            TFA        Scavenger      Reaction time                                        ______________________________________                                         1     95%      5% H.sub.2 O   1.5 h                                            2     95%      5% ethanedithiol/anisol                                                                       1.5 h                                                           (1:3)                                                           ______________________________________                                    

The suspension of the peptide-resin in the suitable TFA mixture was stirred at room temperature for the stated time and then the resin was filtered off and washed with TFA and DCM. The filtrate and the washings were concentrated, and the peptide was precipitated by addition of diethyl ether. After cooling in an ice bath, the precipitate was filtered off, taken up in 30% acetic acid and lyophilized.

V. When an o-chlorotrityl-resin (supplied by Biohellas) is used, the suspension of the peptide-resin in an acetic acid/trifluoroethanol/dichloromethane mixture (1:1:3) is stirred at room temperature for 1 h. The resin is then filtered off with suction and thoroughly washed with the cleavage solution. The combined filtrates are concentrated in acuo and treated with water. The precipitated solid is removed by filtration or centrifugation, washed with diethyl ether and dried under reduced pressure.

FIG. 1: The Boc protective group technique on a polymeric support ##STR35## Boc=t-butyloxycarbonyl protective group PG=side-chain protective group

R=amino-acid side chain

FIG. 2: The Fmoc protective group technique on a polymeric support ##STR36## Fmoc=9-fluorenylmethyloxycarbonyl protective group PG=side-chain protective group

R=amino-acid side chain

VI. Formation of the ester or hydroxylamino linkage

A suitable amino acid or peptide derivative was dissolved in THF, DMF or a mixture of both solvents. After cooling to a temperature between -20° C. and -10° C. 1.5 equivalents of EDCI and 1.5 equivalents of DMAP were added, after stirring for about 1 h 1.5 eq. of the hydroxy- or or hydroxylamino compound was added. The reaction was stirred for 2 h at about 0° C., then for about 24 h at room temperature. After the reaction was complete the mixture was poured into a saturated NaCl-solution and extracted several times with ethylacetate or dichloromethane. The organic phases were combined and evaporated.

VII: Purification and characterization of the peptides

Purification was carried out by gel chromatography (SEPHADEX G-10, G-15/10% HOAc, SEPHADEX LH20/MeOH) with or without subsequent medium pressure chromatography (MPLC) (stationary phase: HD-SIL C-18, 20-45μ, 100 Å; mobile phase: gradient with A=0.1% TFA/MeOH, B=0.1% TFA/H₂ O).

The purity of the resulting products was determined by analytical HPLC (stationary phase: 100 2.1 mm VYDAC C-18, 5 1, 300 Å; mobile phase: CH₃ CN/H₂ O gradient, buffered with 0.1% TFA, 40° C.). Characterization was fast atom bombardment mass spectroscopy.

B. Synthesis of Building Blocks

1. Me₂ Val-Val-MeVal-Pro-Pro-OMe×HCl

a) 234 g (0.463 mol) of Me₂ Val-Val-MeVal-Pro-OMe×HCl were dissolved in a mixture of 2.3 l of toluene and 150 ml of methanol, then 47.7 g (1.157 mol) of NaOH were added and the mixture was stirred at room temperature for about 20 h.

It was then concentrated, 500 ml of CH₂ Cl₂ were added to the residue, and the mixture was again concentrated.

b) The crude product obtained in this way was suspended in 2.5 l of CH₂ Cl₂ and, at +10° C., 178 g (1.76 mol) of triethylamine and 85.5 g (0.71 mol) of pivaloyl chloride were added dropwise. The mixture was stirred at 5°-10° C. for about 1 h and then 77.6 g of H-Pro-OMe×HCl were introduced in portions and the mixture was stirred at 10° C. for 2 h and then at room temperature overnight.

For workup, the mixture was concentrated, the residue was partitioned between 850 ml of H₂ O and 1.1 l of toluene, and the pH was adjusted to about 1.5 with concentrated HCl while stirring.

After separating the phases, 1 l of CH₂ Cl₂ was added to the aqueous phase, the pH was adjusted to 9 with concentrated sodium hydroxide solution, the phases were separated and the aqueous phase was re-extracted. Concentration of the combined organic phases resulted in about 285 g of residue.

c) The resulting residue was dissolved in 1.6 l of isopropanol and, at 40° C., 64 g of isopropanolic HCl (29%) were added, and the mixture was allowed to cool to room temperature with stirring. After about 2 h, the precipitate was filtered off, washed with isopropanol and methyl tert-butyl ether and dried at 50° C. This resulted in 222 g of pentapeptide with a purity of 98.8% (according to HPLC).

2. Me₂ Val-Val-MeVal-Pro-Pro--OH×HCl

222 g (0.367 Mol) of Me₂ Val-Val-MeVal-Pro-Pro-OMe×HCl were dissolved in 700 ml of H₂ O, and 38 g (0.94 mol) of NaOH were added.

After the reaction was complete, the mixture was acidified by adding 61.7 g of concentrated HCl and was then concentrated. The crystalline residue was mixed with 500 ml of CH₃ OH, again concentrated and then stirred with 1 l of acetone at 50° C. The precipitate was filtered off with suction and dried and then dissolved in 1.6 l of acetone and, while stirring, 47.5 g of isopropanol/HCl (30%) were added and the mixture was stirred at room temperature for 2 h. The precipitate obtained in this way was again filtered off with suction, washed with acetone and dried at 50° C.

This resulted in 191.2 g of pure product (99.9% according to HPLC). Melting point: 242° to 244° C.

C. Specific Procedures

General method

1 eq of peptide acid was dissolved together with 1 to 2 eq of the appropriate nucleophile (alcohol, hydroxylamine, oxime) in DMF/THF and, at -10° C., 1 to 2 eq each of DMAP, EDC×HCl and HOBt were added; the mixture was subsequently stirred at -10° C. and then at room temperature. For workup, aqueous NaCl solution is added to the mixture and it is extracted with suitable organic solvents such as CH₂ Cl₂, or the reaction mixture is concentrated directly. The crude product obtained in this way can then be purified by chromatography on silica gel (CH₂ Cl₂ /CH₃ OH as eluent) or MPLC on RP silica gel (CH₃ CN/H₂ O+TFA).

EXAMPLE

I-1 Me₂ Val-Val-MeVal-Pro-Pro cyclohexyl ester

1.2 g (2 mmol) of Me₂ Val-Val-MeVal-Pro-Pro--OH×HCl and 0.27 g (2.7 mmol) of cyclohexanol were dissolved in 50 ml of 4:1 DMF/THF and then, at -10° C., 0.5 g (4.1 mmol) DMAP, 0.43 g (2.2 mmol) of EDC×HCl and 0.34 g (2.2 mmol) of HOBt were successively added. The mixture was then stirred at -10° C. for 2 h and at room temperature overnight. For workup, the reaction mixture was poured into saturated NaCl solution and thoroughly extracted with ethyl acetate. The residue remaining after the combined organic phases had been dried and concentrated was purified on silica gel (eluent CH₂ Cl₂ /CH₃ OH 2%).

This resulted in 0.26 g of the ester as white foam. FAB-MS: 634.5 (M+H⁺).

The following were prepared in a similar way:

I-20 Me₂ Val-Val-MeVal-Pro-Pro-dodecyl ester FAB-MS: 720.5 (M+H⁺)

I-26 Me₂ Val-Val-MeVal-Pro-Pro-octadecyl ester FAB-MS: 804.5 (M+H⁺)

I-89 Me₂ Val-Val-MeVal-Pro-Pro 2-(tert-butyloxycarbonylamino)ethyl ester FAB-MS: 695.5 (M+H⁺)

I-14 Me₂ Val-Val-MeVal-Pro-Pro-hexyl ester FAB-MS: 636.5 (M+H⁺)

I-2 Me₂ Val-Val-MeVal-Pro-Pro-cyclopentyl ester FAB-MS: 620.5 (M+H⁺)

I-58 Me₂ Val-Val-MeVal-Pro-Pro-trans-3-methyl-2-butenyl ester FAB-MS: 620 (M+H⁺)

I-59 Me₂ Val-Val-MeVal-Pro-Pro-trans-3,7-dimethyl-2,6-octadienyl ester FAB-MS: 688.5 (M+H⁺)

I-49 Me₂ Val-Val-MeVal-Pro-Pro-1-adamantanylmethyl ester FAB-MS: 700.4 (M+H⁺)

I-35 M₂ Val-Val-MeVal-Pro-Pro-3-pentyl ester FAB-MS: 630.5 (M+H⁺)

I-64 M₂ Val-Val-MeVal-Pro-Pro-N-methyl-4-piperidyl ester FAB-MS: 649.4 (M+H⁺)

I-62 Me₂ Val-Val-MeVal-Pro-Pro-1,3-difluoro-2-propyl ester FAB-MS: 630.5 (M+H⁺)

I-74 Me₂ Val-Val-MeVal-Pro-Pro-2-hydroxyethyl ester FAB-MS: 654 (M+H⁺)

I-76 Me₂ Val-Val-MeVal-Pro-Pro-2-(methoxyethoxy)ethyl ester FAB-MS: 654 (M+H⁺)

I-78 Me₂ Val-Val-MeVal-Pro-Pro-2-(2-butoxyethoxy)ethyl ester FAB-MS: 696.5 (M+H⁺)

I-79 Me₂ Val-Val-MeVal-Pro-Pro-2-(benzyloxy)ethyl ester FAB-MS: 686 (M+H⁺)

I-75 Me₂ Val-Val-MeVal-Pro-Pro-2-methoxyethyl ester FAB-MS: 610 (M+H⁺)

I-174 Me₂ Val-Val-MeVal-Pro-Pro-2-(4-methyl-5-thiazolyl)ethyl ester FAB-MS: 677.3 (M+H⁺)

I-175 Me₂ Val-Val-MeVal-Pro-Pro(2-methoxycarbonyl-2-methyl)-propyl ester FAB-MS: 666 (M+H⁺)

I-172 Me₂ Val-Val-MeVal-Pro-Pro-(1-methoxycarbonyl-2-methyl)-propyl ester FAB-MS: 666 (M+H⁺)

III-4 M₂ Val-Val-MeVal-Pro-Pro-2-propanone oxime ester FAB-MS: 607 (M+H⁺)

III-34 Me₂ Val-Val-MeVal-Pro-Pro-4-methylbenzaldehyde oxime ester FAB-MS: 669 (M+H⁺)

III-35 M₂ Val-Val-MeVal-Pro-Pro-benzophenone oxime ester FAB-MS: 731.5 (M+H⁺)

The following compounds were prepared or can be prepared according to the example I-1

    A--B--D--E--F--O--R.sub.L                                  (Type I)

    ______________________________________                                         No.  A       B       D     E    F    R.sub.L                                   ______________________________________                                         I-1  Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Cyclohexyl                                I-2  Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Cyclopentyl                               I-3  Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Cyclopropyl                               I-4  Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Cyclobutyl                                I-5  Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Cycloheptyl                               I-6  Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Cyclooctyl                                I-7  Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Cyclononyl                                I-8  Me.sub.2 Val                                                                           Val     Val   Pro  Pro  1-Methylpropyl                            I-9  Me.sub.2 Val                                                                           Val     Val   Pro  Pro  1-Methylbutyl                             I-10 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Cyclodecyl                                I-13 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Pentyl                                    I-14 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Hexyl                                     I-15 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Heptyl                                    I-16 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Octyl                                     I-17 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Nonyl                                     I-18 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Decyl                                     I-19 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Undecyl                                   I-20 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Dodecyl                                   I-21 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Tridecyl                                  I-22 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Tetradecyl                                I-23 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Pentadecyl                                I-24 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Hexadecyl                                 I-25 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Heptadecyl                                I-26 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Octadecyl                                 I-27 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  1-Methylethyl                             I-28 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Methylbutyl                             I-29 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3-Methylbutyl                             I-30 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Methylpropyl                            I-31 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3,3-Dimethylbutyl                         I-32 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2,3-Dimethylbutyl                         I-33 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  4-Methylpentyl                            I-34 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  4,4-Dimethylpentyl                        I-35 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Pent-3-yl                                 I-36 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Hept-4-yl                                 I-37 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2,2-Dimethylbutyl                         I-38 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2,2,2-Trifluoroethyl                      I-39 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  1-Fluoroethyl                             I-40 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2,2-Difluoroethyl                         I-41 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Methylcyclopropyl                         I-42 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Methylcyclobutyl                          I-43 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Methylcyclopentyl                         I-44 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Methylcyclohexyl                          I-45 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Methylcycloheptyl                         I-46 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Methylcyclooctyl                          I-47 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Methylcyclononyl                          I-48 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Methylcyclodecyl                          I-49 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Methyladamantyl                           I-50 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Propenyl                                I-51 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3-Butenyl                                 I-52 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Butenyl                                 I-53 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Methyl-2-propenyl                       I-54 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Pentenyl                                I-55 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3-Methyl-2-propenyl                       1-56 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3-Pentenyl                                I-57 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  4-Pentenyl                                I-58 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3-Methyl-2-butenyl                        I-59 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3,7-Dimethyl-2,6-                                                              octadienyl                                I-60 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3,7,11-Trimethyldo-                                                            deca-2,6,10-trienyl                       I-61 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3,7,11,15-Tetra-                                                               methylhexadeca-                                                                2,6,10,14-tetraenyl                       I-62 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  1,3-Difluoro-prop-                                                             2-yl                                      I-63 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  4-Piperidyl                               I-64 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  N-Methyl-4-piperidyl                      I-65 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  N-Acetyl-4-piperidyl                      I-66 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  N-Formyl-4-piperidyl                      I-67 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  N-tert-Butyl-4-                                                                piperidyl                                 I-68 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  N-tert-Butyloxy-                                                               carbonyl-4-piperidyl                      I-69 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  N-Benzyl-4-piperidyl                      I-70 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  N-Benzyloxycarbonyl-                                                           4-piperidyl                               I-71 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  N-Benzoyl-4-                                                                   piperidyl                                 I-72 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  4-Tetrahydropyranyl                       I-73 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  4-Tetrahydrothienyl                       I-74 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Hydroxyethyl                            I-75 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Methoxyethyl                            I-76 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2(2-Methoxy-ethoxy)-                                                           ethyl                                     I-77 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2- 2-(2-Methoxy-                                                               ethoxy)-ethoxy!ethyl                      I-78 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-(2-Butoxy-ethoxy)-                                                           ethyl                                     I-79 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Benzyloxy-ethyl                         I-80 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Phenyloxy-ethyl                         I-81 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Methylthioethyl                         I-82 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Benzylthioethyl                         I-83 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Phenylthioethyl                         I-84 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Mercaptoethyl                           I-85 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-N,N-Dimethyl-                                                                aminoethyl                                I-86 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-N,N-Diethylamino-                                                            ethyl                                     I-87 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-N-Acetylaminoethyl                      I-88 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-N-Benzoylamino-                                                              ethyl                                     I-89 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-N-tert-Butyloxy-                                                             carbonylamino-ethyl                       I-90 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-N-Benzyloxycarbo-                                                            nylamino-ethyl                            I-91 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-(N-Isopropyl)-                                                               aminoethyl                                I-92 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3-Methoxypropyl                           I-93 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3-Benzyloxypropyl                         I-94 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2,N,N-Diphenylamino-                                                           ethyl                                     I-95 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3-N,N-Dibenzylamino-                                                           propyl                                    I-96 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3-Phenyloxypropyl                         I-97 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3-N,N-Dimethyl-                                                                aminopropyl                               I-98 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3-N-Acetylaminopro-                                                            pyl                                       I-99 Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3-N,N-Diethylamino-                                                            propyl                                    I-100                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3-Methylthiopropyl                        I-101                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Phenylthiopropyl                        I-102                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  3-Benzylthiopropyl                        I-111                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Indol-3-yl)methyl                        I-112                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (N-Methylindol-3-                                                              yl)methyl                                 I-113                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (N-Acetylindol-3-                                                              yl)methyl                                 I-114                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (3-N-Formylindolyl)-                                                           methyl                                    I-115                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (1-Methylimid-                                                                 azolyl)methyl                             I-116                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Thienyl-2-yl)methyl                      I-117                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Benzimidazolyl)-                                                              methyl                                    I-118                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Isoxazol-5-yl)-                                                               methyl                                    I-119                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (3-Methyl-isoxazol-                                                            5-yl)methyl                               I-120                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (3-Methoxymethyl-                                                              isoxazol-5-yl)methyl                      I-121                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (4-Methyl-imidazol-                                                            5-yl)methyl                               I-123                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Furan-2-yl)methyl                        I-124                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Furan-3-yl)methyl                        I-125                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Benzofuran-2-yl)-                                                             methyl                                    I-126                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Thien-3-yl)methyl                        I-127                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (1-Benzylimidazol-3-                                                           yl)methyl                                 I-128                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Thiazol-2-yl)methyl                      I-129                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Benzothiazol-2-yl)-                                                           methyl                                    I-130                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Oxazol-2-yl)methyl                        I-131                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Benzoxazol-2-yl)-                                                             methyl                                    I-132                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Thiazol-4-yl)methyl                      I-133                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Thiazol-5-yl)methyl                      I-134                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (4-Methyl-thiazol-                                                             5-yl)methyl                               I-135                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Oxazol-4-yl)methyl                       I-136                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Oxazol-5-yl)methyl                       I-137                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (2-Phenyloxazol-4-                                                             yl)methyl                                 I-138                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (2-Phenylthiazol-4-                                                            yl)methyl                                 I-139                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (2-Methyl-1,3,4-                                                               thiazol-5-yl)methyl                       I-140                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (2-Phenyl-1,3,4-                                                               thiazol-5-yl)methyl                       I-141                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Naphthylmethyl                            I-142                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  Naphthyl-2-methyl                         I-143                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (4-Fluoro-phenyl)-                                                             methyl                                    I-144                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (4-Methoxy-phenyl)-                                                            methyl                                    I-145                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (4-Trifluoromethyl-                                                            phenyl)methyl                             I-146                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (4-Chlorophenyl)-                                                              methyl                                    I-147                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (3,4-Dimethoxy-                                                                phenyl)methyl                             I-148                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (3,4-Dioxymethylene-                                                           phenyl)methyl                             I-149                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (3,4-Dioxyethylene-                                                            phenyl)methyl                             I-150                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (3-Fluoro-                                                                     phenyl)methyl                             I-151                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (3-Methoxy-                                                                    phenyl)methyl                             I-152                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (3-Trifluoromethyl-                                                            phenyl)methyl                             I-153                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (2-Fluoro-                                                                     phenyl)methyl                             I-154                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (2,6-Difluoro-                                                                 phenyl)methyl                             I-155                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (2-Trifluoromethyl-                                                            phenyl)methyl                             I-156                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (4-tert-Butylphenyl)-                                                          methyl                                    I-157                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (4-Methyl-                                                                     phenyl)methyl                             I-158                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (3-Pyridyl)methyl                         I-159                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (4-Pyridyl)methyl                         I-160                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (2-Pyridyl)methyl                         I-161                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (1-Naphthyl)methyl                        I-162                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (2-Naphthyl)methyl                        I-163                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (4-Quinolinyl)methyl                      I-164                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (5-Quinolinyl)methyl                      I-165                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (3-Methyl-                                                                     phenyl)methyl                             I-166                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Methoxycarbonyl)-                                                             methyl                                    I-167                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Methoxycarbonyl)-2-                                                           ethyl                                     I-168                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Methoxycarbonyl)-3-                                                           propyl                                    I-169                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Methoxycarbonyl)-4-                                                           butyl                                     I-170                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Methoxycarbonyl)-1-                                                           ethyl                                     I-171                                                                               Me.sub.2 Val                                                                           yai     Val   Pro  Pro  (Methoxycarbonyl)-                                                             1,1-dimethyl-2-ethyl                      I-172                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Methoxycarbonyl)-2-                                                           methyl-1-propyl                           I-173                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  (Methoxycarbonyl)-1-                                                           propyl                                    I-174                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-(4-Methyl-5-thiazo                                                           lyl)ethyl                                 I-175                                                                               Me.sub.2 Val                                                                           Val     Val   Pro  Pro  2-Methoxycarbonyl-2-                                                           methylpropyl                              I-401                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Cyclohexyl                                I-402                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Cyclopentyl                               I-403                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Cyclopropyl                               I-404                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Cyclobutyl                                I-405                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Cycloheptyl                               I-406                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Cycloctyl                                 I-407                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Cyclononyl                                I-408                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  1-Methylpropyl                            I-409                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  1-Methylbutyl                             I-410                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Cyclodecyl                                I-413                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Pentyl                                    I-414                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Hexyl                                     I-415                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Heptyl                                    I-416                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Octyl                                     I-417                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Nonyl                                     I-418                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Decyl                                     I-419                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             pro  Pro  Undecyl                                   I-420                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Dodecyl                                   I-421                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Tridecyl                                  I-422                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Tetradecyl                                I-423                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Pentadecyl                                I-424                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Hexadecyl                                 I-425                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Heptadecyl                                I-426                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Octadecyl                                 I-427                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  1-Methylethyl                             I-428                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Methylbutyl                             I-429                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3-Methylbutyl                             I-430                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Methylpropyl                            I-431                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3,3-Dimethylbutyl                         I-432                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2,3-Dimethylbutyl                         I-433                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  4-Methylpentyl                            I-434                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  4,4-Dimethylpentyl                        I-435                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Pent-3-yl                                 I-436                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Hept-4-yl                                 I-437                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2,2-Dimethylbutyl                         I-438                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2,2,2-Trifluoroethyl                      I-439                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  1-Fluoroethyl                             I-440                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2,2-Difluoroethyl                         I-441                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Methylcyclopropyl                         I-442                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Methylcyclobutyl                          I-443                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Methylcyclopentyl                         I-444                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Methylcyclohexyl                          I-445                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Methylcycloheptyl                         I-446                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Methylcyclooctyl                          I-447                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Methylcyclononyl                          I-448                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Methylcyclodecyl                          I-449                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Methyladamantyl                           I-450                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Propenyl                                I-451                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3-Butenyl                                 I-452                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Butenyl                                 I-453                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Methyl-2-propenyl                       I-454                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Pentenyl                                I-455                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3-Methyl-2-propenyl                       I-456                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3-Pentenyl                                I-457                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  4-Pentenyl                                I-458                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3-Methyl-2-butenyl                        I-459                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3,7-Dimethyl-2,6-                                                              octadienyl                                I-460                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3,7,11-Trimethyl-                                                              dodeca-2,6,10-trienyl                     I-461                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3,7,11,15-Tetra-                                                               methylhexadeca-                                                                2,6,10,14-tetraenyl                       I-462                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  1,3-Difluoro-prop-                                                             2-yl                                      I-463                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  4-Piperidyl                               I-464                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  N-Methyl-4-piperidyl                      I-465                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  N-Acetyl-4-piperidyl                      I-466                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  N-Formyl-4-piperidyl                      I-467                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  N-tert-Butyl-4-                                                                piperidyl                                 I-468                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  N-tert-Butyloxycarbon                                                          yl-4-piperidyl                            I-469                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  N-Benzyl-4-piperidyl                      I-470                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  N-Benzyloxycarbonyl-                                                           4-piperidyl                               I-471                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  N-Benzoyl-4-                                                                   piperidyl                                 I-472                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  4-Tetrahydropyranyl                       I-473                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  4-Tetrahydrothienyl                       I-474                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Hydroxyethyl                            I-475                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Methoxyethyl                            I-476                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2(2-Methoxyethoxy)-                                                            ethyl                                     I-477                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2- 2-(2-Methoxy-                                                               ethoxy)ethoxy!ethyl                       I-478                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-(2-Butoxyethoxy)-                                                            ethyl                                     I-479                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Benzyloxyethyl                          I-480                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Phenyloxyethyl                          I-481                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Methylthioethyl                         I-482                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Benzylthioethyl                         I-483                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Phenylthioethyl                         I-484                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Mercaptoethyl                           I-485                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-N,N-Dimethylamino                                                            ethyl                                     I-486                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-N,N-Diethylamino-                                                            ethyl                                     I-487                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-N-Acetylaminoethyl                      I-488                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-N-Benzoylamino-                                                              ethyl                                     I-489                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-N-tert-Butyloxy-                                                             carbonylaminoethyl                        I-490                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-N-Benzyloxycarbon-                                                           ylaminoethyl                              I-491                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-(N-Isopropyl)-                                                               aminoethyl                                I-492                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3-Methoxypropyl                           I-493                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3-Benzyloxypropyl                         I-494                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2,N,N-Diphenylamino-                                                           ethyl                                     I-495                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3-N,N-Dibenzylamino-                                                           propyl                                    I-496                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3-Phenyloxypropyl                         I-497                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3-N,N-Dimethyl-                                                                aminopropyl                               I-498                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3-N-Acetylamino-                                                               propyl                                    I-499                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3-N,N-Diethylamino-                                                            propyl                                    I-500                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3-Methylthiopropyl                        I-501                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  2-Phenylthiopropyl                        I-502                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  3-Benzylthiopropyl                        I-511                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Indol-3-yl)methyl                        I-512                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (N-Methylindol-3-                                                              yl)methyl                                 I-513                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (N-Acetylindol-3-                                                              yl)methyl                                 I-514                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (3-N-Formylindolyl)-                                                           methyl                                    I-515                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (1-Methylimid-                                                                 azolyl)methyl                             I-516                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Thienyl-2-yl)methyl                      I-517                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Benzimidazolyl)-                                                              methyl                                    I-518                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Isoxazol-5-yl)-                                                               methyl                                    I-519                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (3-Methylisoxazol-                                                             5 -yl)methyl                              I-520                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (3-Methoxymethyl-                                                              isoxazol-5-yl)methyl                      I-521                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (4-Methyl-imidazol-                                                            5-yl)methyl                               I-523                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Furan-2-yl)methyl                        I-524                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Furan-3-yl)methyl                        I-525                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Benzofuran-2-yl)-                                                             methyl                                    I-526                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Thienyl-3-yl)methyl                      I-527                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (1-Benzylimidazol-3-                                                           yl)methyl                                 I-528                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Thiazol-2-yl)methyl                      I-529                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Benzothiazol-2-yl)-                                                           methyl                                    I-530                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Oxazol-2-yl)methyl                        I-531                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Benzoxazol-2-yl)-                                                             methyl                                    I-532                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Thiazol-4-yl)methyl                      I-533                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Thiazol-5-yl)methyl                      I-534                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (4-Methyl-thiazol-                                                             5-yl)methyl                               I-535                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Oxazol-4-yl)methyl                       I-536                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Oxazol-5-yl)methyl                       I-537                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (2-Phenyloxazol-4-                                                             yl)methyl                                 I-538                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (2-Phenylthiazol-4-                                                            yl)methyl                                 I-539                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (2-Methyl-1,3,4-                                                               thiazol-5-yl)methyl                       I-540                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (2-Phenyl-1,3,4-                                                               thiazol-5-yl)methyl                       I-541                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Naphthylmethyl                            I-542                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  Naphthyl-2-methyl                         I-543                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (4-Fluoro-phenyl)-                                                             methyl                                    I-544                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (4-Methoxyphenyl)-                                                             methyl                                    I-545                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (4-Trifluoromethyl-                                                            phenyl)methyl                             I-546                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (4-Chlorophenyl)-                                                              methyl                                    I-547                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (3,4-Dimethoxy-                                                                phenyl)methyl                             I-548                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (3,4-Dioxymethylene-                                                           phenyl)methyl                             I-549                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (3,4-Dioxyethylene-                                                            phenyl)methyl                             I-550                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (3-Fluorophenyl)-                                                              methyl                                    I-551                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (3-Methoxy-                                                                    phenyl)methyl                             I-552                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (3-Trifluoromethyl-                                                            phenyl)methyl                             I-553                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (2-Fluorophenyl)-                                                              methyl                                    I-554                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (2,6-Difluorophenyl)-                                                          methyl                                    I-555                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (2-Trifluoromethyl-                                                            phenyl)methyl                             I-556                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (4-tert-Butylphenyl)-                                                          methyl                                    I-557                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (4-Methyl-                                                                     phenyl)methyl                             I-558                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (3-Pyridyl)methyl                         I-559                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (4-Pyridyl)methyl                         I-560                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (2-Pyridyl)methyl                         I-561                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (1-Naphthyl)methyl                        I-562                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (2-Naphthyl)methyl                        I-563                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (4-Quinolinyl)methyl                      I-564                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (5-Quinolinyl)methyl                      I-565                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (3-Methyl-                                                                     phenyl)methyl                             I-566                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Methoxycarbonyl)-                                                             methyl                                    I-567                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Methoxycarbonyl)-2-                                                           ethyl                                     I-568                                                                               Me2yal  Val     tert.Leu                                                                             Pro  Pro  (Methoxycarbonyl)-3-                                                           propyl                                    I-569                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Methoxycarbonyl)-4-                                                           butyl                                     I-570                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Methoxycarbonyl)-1-                                                           ethyl                                     I-571                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Methoxycarbonyl)-                                                             1,1-dimethyl-2-ethyl                      I-572                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Methoxycarbonyl)-2-                                                           methyl-1-propyl                           I-573                                                                               Me.sub.2 Val                                                                           Val     tert.Leu                                                                             Pro  Pro  (Methoxycarbonyl)-1-                                                           propyl                                    I-201                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Cyclohexyl                                I-202                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Cyclopentyl                               I-203                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Cyclopropyl                               I-204                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Cyclobutyl                                I-205                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Cycloheptyl                               I-206                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Cyclooctyl                                I-207                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Cyclononyl                                I-208                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  1-Methylpropyl                            I-209                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  1-Methylbutyl                             I-210                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Cyclodecyl                                I-213                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Pentyl                                    I-214                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Hexyl                                     I-215                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Heptyl                                    I-216                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Octyl                                     I-217                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Nonyl                                     I-218                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Decyl                                     I-219                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Undecyl                                   I-220                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Dodecyl                                   I-221                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Tridecyl                                  I-222                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Tetradecyl                                I-223                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Pentadecyl                                I-224                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Hexadecyl                                 I-225                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Heptadecyl                                I-226                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Octadecyl                                 I-227                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  1-Methylethyl                             I-228                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Methylbutyl                             I-229                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-Methylbutyl                             I-230                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Methylpropyl                            I-231                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3,3-Dimethylbutyl                         I-232                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2,3-Dimethylbutyl                         I-233                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  4-Methylpentyl                            I-234                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  4,4-Dimethylpentyl                        I-235                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Pent-3-yl                                 I-236                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Hept-4-yl                                 I-237                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2,2-Dimethylbutyl                         I-238                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2,2,2-Trifluoroethyl                      I-239                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  1-Fluoroethyl                             I-240                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2,2-Difluoroethyl                         I-241                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Methylcyclopropyl                         I-242                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Methylcyclobutyl                          I-243                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Methylcyclopentyl                         I-244                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Methylcyclohexyl                          I-245                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Methylcycloheptyl                         I-246                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Methylcyclooctyl                          I-247                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Methylcyclononyl                          I-248                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Methylcyclodecyl                          I-249                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Methyladamentyl                           I-250                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Propenyl                                I-251                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-Butenyl                                 I-252                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Butenyl                                 I-253                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Methyl-2-propenyl                       I-254                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Pentenyl                                I-255                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-Methyl-2-propenyl                       I-256                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-Pentenyl                                I-257                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  4-Pentenyl                                I-258                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-Methyl-2-butenyl                        I-259                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3,7-Dimethyl-2,6-                                                              octadienyl                                I-260                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3,7,11-Trimethyl-                                                              dodeca-2,6,10-trienyl                     I-261                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3,7,11,15-Tetramethyl-                                                         hexadeca-2,6,10,14-                                                            tetraenyl                                 I-262                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  1,3-Difluoroprop-                                                              2-yl                                      I-263                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  4-Piperidyl                               I-264                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  N-Methyl-4-piperidyl                      I-265                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  N-Acetyl-4-piperidyl                      I-266                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  N-Formyl-4-piperidyl                      I-267                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  N-tert-Butyl-4-                                                                piperidyl                                 I-268                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  N-tert-Butyloxy-                                                               carbonyl-                                                                      4-piperidyl                               I-269                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  N-Benzyl-4-piperidyl                      I-270                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  N-Benzyloxycarbonyl-                                                           4-piperidyl                               I-271                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  N-Benzoyl-4-piperidyl                     I-272                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  4-Tetrahydropyranyl                       I-273                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  4-Tetrahydrothienyl                       I-274                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Hydroxyethyl                            I-275                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Methoxyethyl                            I-276                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2(2-Methoxyethoxy)-                                                            ethyl                                     I-277                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2- 2-(2-Methoxy-                                                               ethoxy)ethoxy!ethyl                       I-278                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-(2-Butoxyethoxy)-                                                            ethyl                                     I-279                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Benzyloxyethyl                          I-280                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Phenyloxyethyl                          I-281                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Methylthioethyl                         I-282                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Benzylthioethyl                         I-283                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Phenylthioethyl                         I-284                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Mercaptoethyl                           I-285                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-N,N-Dimethyl-                                                                aminoethyl                                I-286                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-N,N-Diethylamino-                                                            ethyl                                     I-287                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-N-Acetylaminoethyl                      I-288                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-N-Benzoylamino-                                                              ethyl                                     I-289                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-N-tert-Butyloxy-                                                             carbonylaminoethyl                        I-290                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-N-Benzyloxycarbon-                                                           ylamino-ethyl                             I-291                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-(N-Isopropyl)-                                                               aminoethyl                                I-292                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-Methoxypropyl                           I-293                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-Benzyloxypropyl                         I-294                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2,N,N-Diphenylamino-                                                           ethyl                                     I-295                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-N,N-Dibenzylamino-                                                           propyl                                    I-296                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-Phenyloxypropyl                         I-297                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-N,N-Dimethyl-                                                                aminopropyl                               I-298                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-N-Acetylamino-                                                               propyl                                    I-299                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-N,N-Diethylamino-                                                            propyl                                    I-300                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-Methylthiopropyl                        I-301                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Phenylthiopropyl                        I-302                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-Benzylthiopropyl                        I-303                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  2-Ethoxyethyl                             I-304                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  3-Ethoxypropyl                            I-305                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  4-Ethoxybutyl                             I-311                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Indol-3-yl)methyl                        I-312                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (N-Methylindol-3-                                                              yl)methyl                                 I-313                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (N-Acetylindol-3-                                                              yl)methyl                                 I-314                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (3-N-Formylindolyl)-                                                           methyl                                    I-315                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (1-Methylimidazo-                                                              lyl)methyl                                I-316                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Thienyl-2-yl)methyl                      I-317                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Benzimidazolyl)-                                                              methyl                                    I-318                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Isoxazol-5-yl)-                                                               methyl                                    I-319                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (3-Methyl-isoxazol-                                                            5-yl)methyl                               I-320                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (3-Methoxymethyl-                                                              isoxazol-5-yl)methyl                      I-321                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (4-Methyl-imidazol-                                                            5-yl)methyl                               I-323                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Furan-2-yl)methyl                        I-324                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Furan-3-yl)methyl                        I-325                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Benzofuran-2-yl)-                                                             methyl                                    I-326                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Thien-3-yl)methyl                        I-327                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (1-Benzylirnidazol-3-                                                          yl)methyl                                 I-328                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Thiazol-2-yl)methyl                      I-329                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Benzothiazol-2-yl)-                                                           methyl                                    I-330                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Oxazol-2-yl)methyl                        I-331                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Benzoxazol-2-yl)-                                                             methyl                                    I-332                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               VaL   Pro  Pro  (Thiazol-4-yl)methyl                      I-333                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Thiazol-5-yl)methyl                      I-334                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (4-Methyl-thiazol-                                                             5-yl)methyl                               I-335                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Oxazol-4-yl)methyl                       I-336                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Oxazol-5-yl)methyl                       I-337                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (2-Phenyloxazol-4-                                                             yl)methyl                                 I-338                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (2-Phenylthiazol-4-                                                            yl)methyl                                 I-339                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (2-Methyl-1,3,4-                                                               thiazol-5-yl)methyl                       I-340                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (2-Phenyl-1,3,4-                                                               thiazol-5-yl)methyl                       I-341                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Naphthylmethyl                            I-342                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  Naphthyl-2-methyl                         I-343                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (4-Fluoro-phenyl)-                                                             methyl                                    I-344                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (4-Methoxyphenyl)-                                                             methyl                                    I-345                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (4-Trifluoromethyl-                                                            phenyl)methyl                             I-346                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (4-Chlorophenyl)-                                                              methyl                                    I-347                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (3,4-Dimethoxy-                                                                phenyl)methyl                             I-348                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (3,4-Dioxymethylene-                                                           phenyl)methyl                             I-349                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (3,4-Dioxyethylene-                                                            phenyl)methyl                             I-350                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (3-Fluorophenyl)-                                                              methyl                                    I-351                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (3-Methoxyphenyl)                                                              methyl                                    I-352                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (3-Trifluoromethyl-                                                            phenyl)methyl                             I-353                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (2-Fluorophenyl)-                                                              methyl                                    I-354                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (2,6-Difluorophenyl)-                                                          methyl                                    I-355                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (2-Trifluoromethyl-                                                            phenyl)methyl                             I-356                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (4-tert-Butylphenyl)-                                                          methyl                                    I-357                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (4-Methylphenyl)-                                                              methyl                                    I-358                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (3-Pyridyl)methyl                         I-359                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (4-Pyridyl)methyl                         I-360                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (2-Pyridyl)methyl                         I-361                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (1-Naphthyl)methyl                        I-362                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (2-Naphthyl)methyl                        I-363                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (4-Quinolinyl)methyl                      I-364                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (5-Quinolinyl)methyl                      I-365                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (3-Methylphenyl)-                                                              methyl                                    I-366                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Methoxycarbonyl)-                                                             methyl                                    I-367                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Methoxycar-                                                                   bonyl)-2-ethyl                            I-368                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Methoxycarbonyl)-3-                                                           propyl                                    I-369                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Methoxycarbonyl)-4-                                                           butyl                                     I-370                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Methoxycarbonyl)-1-                                                           ethyl                                     I-371                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Methoxycarbonyl)-                                                             1,1-dimethyl-2-ethyl                      I-372                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Methoxycarbonyl)-2-                                                           methyl-1-propyl                           I-373                                                                               Me.sub.2 Val                                                                           tert.Leu                                                                               Val   Pro  Pro  (Methoxycarbonyl)-1-                                                           propyl                                    ______________________________________                                    

    ______________________________________                                          ##STR37##                                                                     No.  A       B      D    E    F    R.sup.5.sub.L                                                                         R.sup.6.sub.L                        ______________________________________                                         II-1 Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Phenyl                               II-2 Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Benzyl                               II-3 Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      1-Methylethyl                        II-4 Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      2-Methylpropyl                       II-5 Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      1-Methylpropyl                       II-6 Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      1,1-Dimethyl-                                                                  ethyl                                II-7 Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Ethyl                                II-8 Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Propyl                               II-9 Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Butyl                                II-10                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Hexyl                                II-11                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Cyclopentyl                          II-12                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Cyclohexyl                           II-13                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Cycloheptyl                          II-14                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Pentyl                               II-15                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Trifluoro-                                                                     methyl                               II-16                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (4-Fluoro-                                                                     phenyl)methyl                        II-17                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (4-Chloro-                                                                     phenyl)methyl                        II-18                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (4-Methoxy-                                                                    phenyl)methyl                        II-19                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (4-Trifluoro-                                                                  methyl)phenyl-                                                                 methyl                               II-20                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Cyclopropyl                          II-21                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      2-Propenyl                           II-22                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Cyclooctyl                           II-23                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Cyclononyl                           II-24                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      Cyclodecyl                           II-25                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      2,2-Dimethyl-                                                                  propyl                               II-26                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      tert-Butyl                           II-27                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  Methyl tert-Butyl                           II-28                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  Methyl Methyl                               II-29                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  Ethyl  Ethyl                                II-30                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  Methyl Ethyl                                II-31                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  Propyl Propyl                               II-32                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  Methyl i-Methylethyl                        II-33                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  Phenyl Phenyl                               II-34                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  Benzyl Benzyl                               II-35                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  Trifluoro-                                                                            Trifluoro-                                                              methyl methyl                               II-36                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  (4-Chloro-                                                                            (4-Chloro-                                                              phenyl)-                                                                              phenyl)methyl                                                           methyl                                      II-37                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  (4-Tri (4-Trifluoro-                                                           fluoro-                                                                               methylphenyl)-                                                          methyl-                                                                               methyl                                                                  phenyl)-                                                                       methyl                                      II-38                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (3-Fluoro-                                                                     phenyl)methyl                        II-39                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (3-Chloro-                                                                     phenyl)methyl                        II-40                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (3-Methoxy-                                                                    phenyl)methyl                        II-41                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (4-tert-Butyl-                                                                 phenyl)methyl                        II-42                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (4-Methyl-                                                                     phenyl)methyl                        II-43                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (3-Methoxy-                                                                    phenyl)methyl                        II-44                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (2-Fluoro-                                                                     phenyl)methyl                        II-45                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (2-Trifluoro-                                                                  methylphenyl)-                                                                 methyl                               II-46                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (3-Trifluoro-                                                                  methylphenyl)-                                                                 methyl                               II-47                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (2,6-Difluoro-                                                                 phenyl)methyl                        II-48                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (3,4-Di-                                                                       methoxy-                                                                       phenyl)methyl                        II-49                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  H      (3,4-Dioxy-                                                                    methylene-                                                                     phenyl)-                                                                       methyl                               II-50                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  Methyl Phenyl                               II-51                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro  Ethyl  Phenyl                               ______________________________________                                         No.  A       B      D    E    F    R.sup.5.sub.L and R.sup.6.sub.L                                                together                                    ______________________________________                                         II-53                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro                                                                                  ##STR38##                                  II-54                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro                                                                                  ##STR39##                                  II-55                                                                               Me.sub.2 Val                                                                           Val    Val  Pro  Pro                                                                                  ##STR40##                                  ______________________________________                                    

    __________________________________________________________________________      ##STR41##                                                                     No.                                                                               A   B  D  E  F  R.sup.5.sub.L                                                                      R.sup.6.sub.L                                           __________________________________________________________________________     III-1                                                                             Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Methyl                                                  III-2                                                                             Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Ethyl                                                   III-3                                                                             Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Propyl                                                  III-4                                                                             Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             Methyl                                                  III-5                                                                             Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             Ethyl                                                   III-6                                                                             Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Ethyl                                                                              Ethyl                                                   III-7                                                                             Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Phenyl                                                  III-8                                                                             Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   4-Fluorophenyl                                          III-9                                                                             Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   4-Chlorophenyl                                          III-10                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   4-Methoxyphenol                                         III-11                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   4-Trifluoro-                                                                   methylphenyl                                            III-12                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   4-tert-Butyl-                                                                  phenyl                                                  III-13                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   3-Fluorophenyl                                          III-14                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   3-Chlorophenyl                                          III-15                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   3-Methoxyphenyl                                         III-16                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   3-Trifluoro-                                                                   methylphenyl                                            III-17                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   2-Fluorophenyl                                          III-18                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   2-Trifluoro-                                                                   methylphenyl                                            III-19                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   tert-Butyl                                              III-20                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             tert-Butyl                                              III-21                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   2,6-Difluoro-                                                                  phenyl                                                  III-22                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   2-Methylpropyl                                          III-23                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   2,2-Dimethyl-                                                                  propyl                                                  III-24                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Butyl                                                   III-25                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Pentyl                                                  III-26                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Hexyl                                                   III-27                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Heptyl                                                  III-28                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Octyl                                                   III-29                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Nonyl                                                   III-30                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Cyclopropyl                                             III-31                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Cyclobutyl                                              III-32                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Cyclopentyl                                             III-33                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Cyclohexyl                                              III-34                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   4-Methylphenyl                                          III-35                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Phenyl                                                                             Phenyl                                                  III-36                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   1-Naphthyl                                              III-37                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   2-Naphthyl                                              III-38                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             1-Naphthyl                                              III-39                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             2-Naphthyl                                              III-40                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             Phenyl                                                  III-41                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             4-Fluorophenyl                                          III-42                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             4-Chlorophenyl                                          III-43                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             4-Methoxyphenyl                                         III-44                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             4-Trifluoro-                                                                   methylphenyl                                            III-45                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             4-Methylphenyl                                          III-46                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             4-tert-Butyl-                                                                  phenyl                                                  III-47                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             3,4-Dimethoxy-                                                                 phenyl                                                  III-48                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   3,4-Dimethoxy-                                                                 phenyl                                                  III-49                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             3-Fluorophenyl                                          III-50                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             3-Chlorophenyl                                          III-51                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             3-Methoxyphenyl                                         III-52                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             3-Trifluoro-                                                                   methylphenyl                                            III-53                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             2-Fluorophenyl                                          III-54                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             2-Chlorophenyl                                          III-55                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             2-Trifluoro-                                                                   methylphenyl                                            III-56                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             2,6-Difluoro-                                                                  phenyl                                                  III-57                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Tri-                                                                               Phenyl                                                                     fluoro-                                                                        methyl                                                      III-58                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Tri-                                                                               2-Naphthyl                                                                 fluoro-                                                                        methyl                                                      III-59                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Tetrahydro-2-                                                                  furanyl                                                 III-60                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Tetrahydro-3-                                                                  furanyl                                                 III-61                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   2-Thienyl                                               III-62                                                                            Me.sub.2 Val                                                                       Va1                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   Tetrahydro-2-                                                                  furanyl                                                 III-63                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   3-Thienyl                                               III-64                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   5-Methyl-                                                                      imidazol-4-yl                                           III-65                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   3-Indolyl                                               III-66                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             2-Thioenyl                                              III-67                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             2-Pyrrolyl                                              III-68                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             Thiazol-4-yl                                            III-69                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             Oxazol-4-yl                                             III-70                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   2-Phenyl-                                                                      thiazol-4-yl                                            III-71                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             2-Phenyl-                                                                      thiazol-4-yl                                            III-72                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   2-Phenyl-                                                                      oxazol-4-yl                                             III-73                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             2-Phenyl-                                                                      oxazol-4-yl                                             III-74                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   2-Pyrrolyl                                              III-76                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             2-Pyrrolyl                                              III-77                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   N-Methyl-2-                                                                    pyrrolyl                                                III-78                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             Benzo-2-furyl                                           III-79                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             2-Thiophenyl                                            III-80                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             3-Thiophenyl                                            III-81                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   3-Phenyl-                                                                      isoxazol-5-yl                                           III-82                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   3-Methyl-                                                                      isoxazol-5-yl                                           III-83                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   3-Isopropyl-5-                                                                 isoxazolyl                                              III-84                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             3-Phenyl-                                                                      isoxazol-5-yl                                           III-85                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             3-Methyl-                                                                      isoxazol-5-yl                                           III-86                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Cyclo-                                                                             2-Thienyl                                                                  propyl                                                      III-87                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             Imidazol-4-yl                                           III-88                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   4-Pyridyl                                               III-89                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   3-Pyridyl                                               III-90                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   2-Pyridyl                                               III-91                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             4-Pyridyl                                               III-92                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             3-Pyridyl                                               III-93                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             2-Pyridyl                                               III-94                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   4-Quinolinyl                                            III-95                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             4-Quinolinyl                                            III-96                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               H   5-Quinolinyl                                            III-97                                                                            Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Methyl                                                                             5-Quinolinyl                                            III-109                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Cyclopropyl                                                 III-110                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Cyclobutyl                                                  III-111                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Cyclopentyl                                                 III-112                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Cyclohexyl                                                  III-113                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Cycloheptyl                                                 III-114                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Cyclooctyl                                                  III-115                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Cyclononyl                                                  III-116                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               Cyclodecyl                                                  III-117                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               4-Piperidyl                                                 III-118                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               4-Pyranyl                                                   III-119                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                               4-Thiophenyl                                                III-120                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                                ##STR42##                                                  III-121                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                                ##STR43##                                                  III-122                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                                ##STR44##                                                  III-123                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                                ##STR45##                                                  III-122                                                                           Me.sub.2 Val                                                                       Val                                                                               Val                                                                               Pro                                                                               Pro                                                                                ##STR46##                                                  __________________________________________________________________________

D. Biological Evaluation

1. In vitro methodology

Cytotoxicity may be measured using a standard methodology for adherent cell lines such as the microculture tetrazolium assay (MTT). Details of this assay have been published (Alley, MC et al, Cancer Research 48:589-601, 1988). Exponentially growing cultures of tumor cells such as the HT-29 colon carcinoma or LX-1 lung tumor are used to make microtiter plate cultures. Cells are seeded at 5000-20,000 cells per well in 96-well plates (in 150 μl of media), and grown overnight at 37° C. Test compounds are added, in 10-fold dilutions varying from 10⁻⁴ M to 10⁻¹⁰ M. Cells are then incubated for 48 hours. To determine the number of viable cells in each well, the MTT dye is added (50 μl of 3 mg/ml solution of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide in saline). This mixture is incubated at 37° C. for 5 hours, and then 50 μl of 25% SDS, pH2 is added to each well. After an overnight incubation, the absorbance of each well at 550 nm is read using an ELISA reader. The values for the mean +/- SD of data from replicated wells are calculated, using the formula % T/C (% viable cells treated/control). ##EQU1##

The concentration of test compound which gives a T/C of 50% growth inhibition was designated as the IC₅₀

2. In vivo methodology

Compounds of this invention may be further tested in any of the various pre-clinical assays for in vivo activity which are indicative of clinical utility. Such assays are conducted with nude mice into which tumor tissue, preferably of human origin, has been transplanted ("xenografted"), as is well known in this field. Test compounds are evaluated for their anti-tumor efficacy following administration to the xenograft-bearing mice.

More specifically, human tumors which have been grown in athymic nude mice are transplanted into new recipient animals, using tumor fragments which are about 50 mg in size. The day of transplantation is designated as day 0. Six to ten days later, mice are treated with the test compounds given as an intravenous or intraperitoneal injection, in groups of 5-10 mice at each dose.

Compounds were given daily for 5 days, 10 days or 15 days, at doses from 10-100 mg/kg body weight. Tumor diameters and body weights were measured twice weekly. Tumor volumes are calculated using the diameters measured with Vernier calipers, and the formula:

    (length×width.sup.2)/2=mg of tumor weight

Mean tumor weights are calculated for each treatment group, and T/C values determined for each group relative to the untreated control tumors.

The novel compounds of the present invention show good in vitro activity in the above mentioned assay systems and antitumor activity in the above mentioned in vivo system. 

We claim:
 1. A peptide of the formula I

    A--B--D--E--F--L                                           (I)

and the salts thereof with physiologically tolerated acids, wherein: A is of Formula II_(A), ##STR47## wherein R_(A) is hydrogen, C₁₋₃ -alkyl, C₁₋₃ -alkyl which is substituted by 1 to 3 fluorine atoms, cyclopropyl, or cyclopropyl which is substituted by 1 to 3 fluorine atoms;R¹ _(A) is C₁₋₃ -alkyl, C₁₋₃ -alkyl which is substituted by 1 to 3 fluorine atoms, cyclopropyl, or cyclopropyl which is substituted by 1 to 3 fluorine atoms; R² _(A) is C₁₋₅ -alkyl, C₁₋₅ -alkyl which is substituted by 1 to 3 fluorine atoms, C₃₋₅ -cycloalkyl, or C₃₋₅ -cycloalkyl which is substituted by 1 to 3 fluorine atoms; B is of Formula II_(B), ##STR48## wherein T is an NH group,R¹ _(B) is a hydrogen; R² _(B) is C₁₋₆ -alkyl, C₃₋₆ -cycloalkyl, methoxymethyl, 1-methoxyethyl or 1-methylvinyl; or R¹ _(B) and R² _(B) together are an isopropylidene group; or T is an oxygen atom, R¹ _(B) is hydrogen and R² _(B) is C₁₋₆ -alkyl; D is of Formula II_(D), ##STR49## wherein R_(D) is hydrogen, C₁₋₃ -alkyl, C₁₋₃ -alkyl which is substituted by 1 to 3 fluorine atoms, cyclopropyl, or cyclopropyl which is substituted by 1 to 3 fluorine atoms;R¹ _(D) is hydrogen; and R² _(D) is C₁₋₅ -alkyl, cyclopropyl, methoxymethyl, 1-methoxyethyl or 1-methylvinyl; E is of Formula II_(E) ##STR50## wherein n_(E) is 0, 1 or 2;R¹ _(E) is hydrogen, C₁₋₃ -alkyl, C₁₋₃ -alkyl which is substituted by 1 to 3 fluorine atoms, cyclopropyl, or cyclopropyl which is substituted by 1 to 3 fluorine atoms; R² _(E) and R³ _(E) are, independently of one another, hydrogen or a methyl group; R⁴ _(E) is hydrogen, a hydroxy, methoxy or ethoxy group or a fluorine atom; and R⁵ _(E) is hydrogen or a fluorine atom; or n_(E) is 1 and R³ _(E) and R⁴ _(E) together are a bond; or R⁴ _(E) and R⁵ _(E) are a doubly bonded oxygen radical; or n_(E) is 2 and R¹ _(E) and R² _(E) together are a bond; or E is of Formula III_(E), ##STR51## wherein R_(E) is hydrogen or a methyl or ethyl group; andR¹ _(E) is hydrogen, C₁₋₃ -alkyl, C₁₋₃ -alkyl which is substituted by 1 to 3 fluorine atoms, cyclopropyl, or cyclopropyl which is substituted by 1 to 3 fluorine atoms; or E is of Formula IV_(E) ##STR52## wherein X_(E) is an oxygen or a sulfur atom; andR1_(E) is hydrogen, C₁₋₃ -alkyl, C₁₋₃ -alkyl which is substituted by 1 to 3 fluorine atoms, cyclopropyl, or cyclopropyl which is substituted by 1 to 3 fluorine atoms; F is of Formula II_(F), ##STR53## wherein n_(F) is 0, 1 or 2;R¹ _(F) is hydrogen, C₁₋₃ -alkyl, C₁₋₃ -alkyl which is substituted by 1 to 3 fluorine atoms, cyclopropyl, or cyclopropyl which is substituted by 1 to 3 fluorine atoms; R² _(F) and R³ _(F) are, independently of one another, hydrogen or a methyl group; R⁴ _(F) is hydrogen, a hydroxy, methoxy or ethoxy group or a fluorine atom; and R⁵ _(F) is hydrogen or a fluorine atom; or n_(F) is 1 and R³ _(F) and R⁴ _(E) together are a bond; or F is of Formula III_(F), ##STR54## wherein R¹ _(F) is hydrogen, C₁₋₃ -alkyl, C₁₋₃ -alkyl which is substituted by 1 to 3 fluorine atoms, cyclopropyl, or cyclopropyl which is substituted by 1 to 3 fluorine atoms;R² _(F) and R³ _(F) are, independently of one another, hydrogen or a methyl group; R⁴ _(F) is hydrogen, a hydroxy, methoxy or ethoxy group of a fluorine atom; and R⁵ _(F) is hydrogen or a fluorine atom or n_(E) is 1 and R³ _(F) and R⁴ _(F) together are a bond; or F is of Formula IV_(F), ##STR55## wherein X_(F) is oxygen or sulfur; andR¹ _(F) is hydrogen, C₁₋₃ -alkyl, C₁₋₃ -alkyl which is substituted by 1 to 3 fluorine atoms, cyclopropyl, or cyclopropyl which is substituted by 1 to 3 fluorine atoms; or F is an N-methylglycyl, N-ethylglycyl, N-methylalanyl or N-ethylalanyl residue; and L is a substituted or unsubstituted, C¹ -C₁₈ alkoxy, aryloxy, hydroxylamino, or oxime group.
 2. A peptide of the formula I as claimed in claim 1, whereL is a radical of the formula I_(L)

    --O--R.sub.L                                               (I.sub.L)

whereR_(L) is C₃₋₁₀ -cycloalkyl, a C₂₋₁₈ -methylalkenyl or C₅₋₁₆ -alkyl, C₁₋₅ -alkylcarboxy-C₁₋₁₀ -alkyl which may be substituted by 1 to 5 halogen atoms; or R_(L) is the radical --(CH₂)_(aL) --R_(L) ¹, wherea_(L) is 1, 2 or 3, and R_(L) ¹ is a saturated or partially unsaturated C₃₋₁₀ -carbocycle, or a saturated or partially unsaturated cyclic radical which, besides carbon atoms, contains as ring members hetero atoms from the group consisting of oxygen, sulfur or nitrogen, it being possible in saturated systems for the nitrogen additionally to be bonded to a C₁₋₄ -alkyl, C₁₋₄ -acyl, C₁₋₄ -alkoxyacyl group, a benzyl or benzoyl group; or R_(L) is the radical -- CH₂ --CH═C(CH₃)--CH₂ !_(bL) --H whereb_(L) is 1, 2, 3 or 4; or R_(L) is --(CH₂ --CH₂ --O)_(dL) --CH₃ wheredL is 1, 2, 3, 4 or 5; or R_(L) is --(CH₂)_(eL) -aryl or --(CH₂)_(eL) -hetaryl (with the restriction that R_(L) is not benzyl), it being possible for the aryl or hetaryl radical to be substituted or unsubstituted, and _(eL) is 0, 1, 2 or 3; or R_(L) is a radical of the formula

    --(CH.sub.2).sub.fL --W.sub.L --R.sub.L.sup.2              (II.sub.L)

wherefL is 2, 3 or 4, W_(L) is a bridge formed from oxygen, sulfur or the ##STR56## where R_(L) ² is hydrogen, C₁₋₄ -alkyl-, C₃₋₇ -cycloalkyl or substituted or unsubstituted aryl or methylaryl,R_(L) ³ is hydrogen, C₁₋₄ -alkyl, C₃₋₇ -cycloalkyl, C₁₋₁₈ -alkanoyl, benzoyl, carbonyloxy-C₁₋₄ -alkyl, carbonyloxybenzyl or substituted or unsubstituted aryl or methylaryl; or R_(L) is a radical of the formula

    --(CH.sub.2).sub.gL --Z.sub.L                              (III.sub.L)

whereg_(L) is 2, 3 or 4 and Z_(L) is formyl, aminocarbonyl, hydrazinocarbonyl or an acyclic or cyclic acetal or thioacetal radical; or R_(L) is a radical of the formula ##STR57## where g_(L) has the abovementioned meaning, andR_(L) ⁴ has the meaning of glycol residues of the formula--O--(CH₂ --CH₂)_(hL) --CH₃, where h_(L) is a number from 40 to 90,and the salts thereof with physiologically tolerated acids.
 3. A peptide of the formula I as claimed in claim 1, where L is ##STR58## where R_(L) ⁵ is hydrogen, C₁ -C₈ -alkyl which can be substituted by up to 6 halogen atoms, preferably fluorine, C₃₋₁₀ -cycloalkyl, C₁₋₄ -alkyl-C₃₋₁₀ - cycloalkyl, substituted or unsubstituted aryl or hetaryl or C₁₋₄ -alkylaryl which can be substituted by 1 to 5 halogen atoms, andR_(L) ⁶ is C₁ -C₈ -alkyl which can be substituted by up to 6 halogen atoms, preferably fluorine, C₃₋₁₀ -cycloalkyl, C₁₋₄ -alkyl-C₃₋₁₀ - cycloalkyl, substituted or unsubstituted aryl or hetaryl or C₁₋₄ -alkylaryl which can be substituted by 1 to 5 halogen atoms, ##STR59## forms a 5-, 6- or 7-membered heterocycle, and the salts thereof with physiologically tolerated acids.
 4. A peptide of the formula I as claimed in claim 1, whereL is an oxime residue of the formula VI_(L) ##STR60## where R_(L) ⁵ and R_(L) ⁶ each have the abovementioned meanings, or ##STR61## together form a 3- to 7-membered cyclic system which may be aromatic-fused, and the salts thereof with physiologically tolerated acids.
 5. A peptide of the formula I

    A--B--D--E--F--L                                           (I)

and the salts thereof with physiologically tolerated acids, wherein: A is N,N-dimethylvalyl; B is valyl or tert-leucyl; D is valyl or tert-leucyl; E and F are each prolyl; and L is a substituted or unsubstituted C₁ -C₁₈ alkoxy, aryloxy, hydroxylamino, or oxime group. 